Susceptibility to fungal pathogens is primarily restricted to immunocompromised individuals, despite ubiquitous nature of fungal pathogens in the environment. As the initial barrier to pathogenesis, the innate immune response is an integral component of disease prevention. Dectin-1 is an innate immune receptor expressed by phagocytic cells that recognizes fungal cell wall b-glucan. Through in vitro and in vivo experimental examination of knockout mice, a role has been established for the Dectin-1 signaling pathway in the phagocytosis, production of reactive oxygen, and induction of cytokines. The absence of a similar set of genetic tools in humans has hampered our comprehension of Dectin-1's significance during fungal infection in humans. However, we believe that genome-wide association screens in humans provide a valuable tool that can not only inform our understanding the biochemistry of innate immune pathways but also serves as source of genetically diverse biological samples for directly examining the functional consequences of altered innate immunity in humans. Therefore, in this application we propose two specific aims. In specific aim 1 we will characterize 5 polymorphisms in Dectin-1 that we expect will alter the level of expression or the ability of Dectin-1 to recognize its ligand. Specific aim 2 will examine 2 polymorphisms in the gene encoding CARD9, a signaling molecule downstream of Dectin-1, that we predict will be associated with altered CARD9 expression or function. For both specific aims, we propose in vitro experiments to characterize affects of the polymorphisms in Dectin-1 and CARD9 on the recognition, phagocytosis, and transcriptional responses to fungal pathogens in an isolated cell culture system. We will pair these in vitro biochemical and mechanistic studies with the isolation and characterization of primary cells from donors known to posses each of the polymorphisms. Studying the recognition and response to fungal pathogens by genetically defined primary cells will provide us with an understanding of Dectin-1's contribution to the recognition and control of fungal infection by the human innate immune system. PUBLIC HEALTH RELEVANCE: Fungal infections are common in cancer patients and AIDS patients among others, and inflammation activated by white blood cells is critical to mount a successful immune defense. A protein called Dectin-1 recognizes fungal pathogens and triggers inflammation through a signaling molecule called CARD9. We have discovered significant genetic variability between humans in the genes for these two proteins. In this project we will fully characterize the effects of these genetic variants on the molecular mechanisms of signaling.